帕金森病的致病因素及治疗
Pathogenic Factors and Treatment of Parkinson’s Disease

作者: 姜育辉 :南通大学医学院,江苏 南通;南通大学,教育部/江苏省神经再生重点实验室/神经再生协同创新中心,江苏 南通; 刘晓宇 , 杨宇民 :南通大学,教育部/江苏省神经再生重点实验室/神经再生协同创新中心,江苏 南通; 周胜鸾 :南通大学医学院,江苏 南通;

关键词: 帕金森病α-突触核蛋白运动功能障碍康复治疗 Parkinson’s Disease α-Synuclein Motor Dysfunction Rehabilitation Therapy

摘要:
帕金森病(Parkinson’s disease, PD),是继阿兹海默症之后的第二大神经退行性疾病。据统计,全球超过一半的帕金森病患者都是中国人,帕金森病已经成为继心血管疾病、肿瘤之后的我国中老年人的第三杀手。根据起源,该病主要分遗传性和特发性两种。帕金森病患者神经病理学特征常表现为大脑黑质区域多巴胺能神经元的缺失和特定神经元内α-突触核蛋白(α-syn)的沉积。帕金森病主要表现为一系列的运动功能障碍,如震颤、僵直、姿势和步态异常等。帕金森病的发病机理涉及多种因素,如线粒体功能障碍、氧化应激、神经炎症等,现在仍然未有定论,因此也未有药物可以完全的抑制疾病的进程和治愈疾病,现多用左旋多巴和多巴胺激动剂治疗PD,也会辅助一些物理康复治疗。所以,如何在多致病因素的情况下寻找到治疗的有效方法是未来研究中的大挑战,同时也是研究的热点。

Abstract: Parkinson’s disease (PD) is the second largest neurodegenerative disease after Alzheimer’s disease. According to statistics, more than half of the patients with Parkinson’s disease in the world are Chinese. Parkinson’s disease has become the third killer of middle-aged and elderly people in China after cardiovascular diseases and tumors. According to the origin, the disease is mainly divided into hereditary and idiopathic. The neuropathological characteristics of patients with Parkinson’s disease are often manifested in the absence of dopaminergic neurons in the substantia nigra and α-Synuclein deposition in specific neurons. Parkinson’s disease is mainly characterized by a series of motor dysfunction, such as tremor, stiffness, abnormal posture and gait and so on. The pathogenesis of Parkinson’s disease involves many factors, such as mitochondrial dysfunction, oxidative stress, neuroinflammation, etc. There is still no final conclusion. Therefore, there is no drug that can completely inhibit the process of the disease and cure the disease. Now, levodopa and dopamine agonists are used to treat PD, and some physical rehabilitation treatments will also be assisted. Therefore, how to find an effective treatment in the case of multiple pathogenic factors is not only a great challenge in future research, but also a research hotspot.

1. 引言

帕金森病(Parkinson’s disease, PD),是继阿兹海默症之后的第二大神经退行性疾病 [1]。1817年,James Parkinson首先报道了这种疾病,也因此而命名 [2]。据统计,全球有一半的帕金森病患者在中国,帕金森病已经成为继心血管疾病、肿瘤之后的我国中老年人的第三杀手。世界卫生组织专家预测,中国2030年的帕金森病患者将达到500万,患病人群年龄主要集中在65岁以上 [3],男性高于女性 [4]。

根据起源,该病主要分遗传性和特发性两种 [5]。帕金森病患者神经病理学特征常表现为大脑黑质区域多巴胺能神经元的缺失和特定神经元内α-突触核蛋白(α-syn)的沉积 [6],这两种神经性病理也共同应用于帕金森疾病的确诊。

在疾病的早期,与中脑其他区域相比,多巴胺能神经元的缺失主要发生在腹外侧的黑质区域 [7]。到了疾病晚期,在大脑的普遍区域都发生了缺失 [8]。同时,疾病早期发生的缺失说明在运动症状还未出现之前,大脑在此区域已经发生了退化 [8]。另一显著病理特征是α-突触核蛋白(α-syn)在大脑不同区域神经元胞质内不同程度的异常沉积 [9]。大量的α-突触核蛋白(α-syn)沉积构成了路易小体,随着疾病的发展,所能检测到的路易小体的表达逐渐增多,且有向大脑其他区域转移的趋势,造成大脑的多区域退化 [10]。

帕金森病主要症状表现为一系列的运动功能受损,如震颤、僵直、姿势和步态异常等 [2]。除此之外,大多数帕金森病患者也存在许多非运动症状,包括睡眠障碍、认知障碍(如记忆恢复缺陷、痴呆和幻觉等)、情绪障碍、自主功能障碍(主要是起立性低血压)、泌尿生殖功能障碍、胃肠道功能障碍(如便秘)、多汗症、以及一些感觉症状(主要表现为嗅觉减退)和疼痛 [11]。因此大大增加了机体的负担,也对帕金森病的治疗有了更大的挑战。此外,帕金森病的发病机理涉及多种因素,现在仍然未有定论,因此也未有药物可以完全的抑制疾病的进程和治愈疾病,现多用左旋多巴和多巴胺激动剂治疗PD [12] [13],也会辅助一些物理康复治疗 [14] [15]。所以,如何在多致病因素的情况下寻找到治疗的有效方法是未来研究中的大挑战,同时也是研究的热点。

2. 致病因素

2.1. 年龄、性别

帕金森病的患病率与年龄有极大的相关性 [2],调查显示,在50岁之前,帕金森病是罕见的,第六十年至第九十年患病率增加了5~10倍,其中年龄在65岁以上的人群更易患病,患病率约为2%~3% [16]。随着医疗事业的发展,人口趋向于老年化,加剧了患病的基数。帕金森病在发病的第一个十年死亡率并没有明显的增加,而在随后的时间里,死亡率急剧增加 [17]。

除了年龄的相关性,性别似乎也表现出差异,男性发病率为女性的两倍 [5],但女性死亡率更高,病情进展更快。荷兰学者的研究显示,女性帕金森病发病年龄比男性晚约2年,这种差异可能与女性的雌激素有关,主要是由于雌二醇的活性 [18]。此外,女性的发病年龄与经产次数、绝经年龄以及生育期时间呈正相关,具体相关性有待进一步的探究。也有研究表明接触农药、溶剂和金属等特定职业群体患帕金森病的风险增加,而从事此类职业的人以男性居多,这也是导致男性的患病率高于女性的原因之一。

2.2. 环境及生活方式

居住的环境可能会影响帕金森病的患病率。有研究报道,生活在夏威夷的日本人和冲绳人患有帕金森病的比率要比生活在日本的日本人更高,具体的原因还不可知,也许是基因和环境交互的因素 [19]。除此之外,长期从事农业的工作者因经常暴露于有毒杀虫剂的环境中,患病的机率也是相较于其他从业者更高 [20]。此外,长期生活在污染的环境和食用受到污染的食物也会增加患病机率。作为杀虫剂的鱼藤酮在生物研究中现已作为构建帕金森疾病模型的一种物质,它是一种天然的线粒体复合物I抑制剂,通过作用于线粒体对多巴胺能神经元具有高度选择性毒性 [21]。而令人惊奇的是,长期吸烟的人和长期食用咖啡因食物的人患病的机率是较低的 [3] [22]。

体育运动是影响帕金森病发病进展及严重程度的一个重要的生活方式因素。较大的活动量及适当的运动周期可以降低帕金森病的患病风险,并且有助于疾病预后。年轻人较老年人运动量大,患病老年人尤其是老年女性运动量较少,这也可能是影响帕金森病发病年龄以及患病女性病情进展更快的交互因素之一。

2.3. 遗传

在所有的帕金森病患病病例中,遗传性病例占总体患病的5%~10%,大型全基因组关联研究(Genome wide association study, GWAS)证实了遗传性PD中的一些作用基因同时也会影响散发性PD [23],如LRRK2、SNCA、PINK1、DJ-1等。这些病例的研究为散发性PD的神经病理研究提供了关键的线索。也有研究表明,年轻的帕金森病患者的遗传倾向更大,11%~20%的年轻型帕金森病患者有阳性家族史 [24]。

2.4. α-突触核蛋白(α-syn)的蛋白稳态

在PD病人中发现,脑内的α-syn是处于大量聚集的状态,说明α-syn是PD研究中的一个关键点 [25]。在神经毒性的作用下,可溶性的α-syn经过一系列变化逐渐转变为不可溶性α-syn,构成路易小体。随着疾病的发展,所能检测到的路易小体的表达逐渐增多,且有向大脑其他区域转移的趋势,造成大脑的多区域退化 [10]。根据遗传性PD的研究,可能是由于编码α-syn的SNCA基因发生了点突变 [23]。而从蛋白质的降解来看,α-syn在细胞内的蛋白稳态是由机体的泛素–蛋白酶体系统(LAS)和溶酶体–自噬系统维持的 [26],随着年龄的增长,泛素–蛋白酶体系统(LAS)和溶酶体–自噬系统功能逐渐衰退,导致中脑黑质部位的α-syn表达显著增加 [27]。因此,如何维持α-syn的蛋白稳态就显得尤为重要,也是帕金森病研究和治疗的作用靶点之一。

2.5. 线粒体功能障碍

从帕金森病人分离的组织中发现,线粒体电子呼吸链中线粒体复合物I的活性是减弱的 [28],这种缺陷将导致ATP的合成能力减弱,线粒体能量代谢发生障碍,从而导致细胞受到损害 [29]。此外,线粒体内α-syn的聚集也会影响线粒体的功能,在正常的线粒体内,α-syn呈现一个低表达的状态,而线粒体α-syn过度积累则会导致线粒体复合物I的缺陷和氧化应激,从而导致线粒体功能紊乱,细胞受到损伤 [28]。MPP+作为一种线粒体呼吸链的抑制剂,在线粒体持续堆积后会抑制线粒体复合物I [30],从而导致其功能紊乱,神经元受到损伤,营造PD样症状,因而作为生物研究中的一种帕金森病的造模物质。

2.6. 氧化应激

有证据表明,氧化应激作为线粒体功能损害的一种结果在PD病人的大脑内是呈现的一个高度状态 [31]。但这种因素主要作用在死亡神经元的早期还是晚期仍是具有较大的争议性的。其中,在遗传性PD中所提到的DJ-1在其中表现出重要作用,突变的DJ-1编码一种假抗氧化基因,导致早发性常染色体隐性帕金森病,这与细胞内增加的氧化应激是密不可分的 [32] [33]。此外,现已有多篇文献报道,黑质中的多巴胺能神经元极易受到能量代谢和氧化应激的影响 [34],从而导致帕金森病发病。

2.7. 神经炎症

大量尸检、脑成像、生物标记物检测显示神经炎症可能是PD的一个显著性特征之一 [35]。尽管它可能不是最初的诱发因素,但极有可能是一个致病因素 [36]。GWAS显示的与PD风险相关的基因如LRRK2,在免疫细胞中有表达且参与免疫调节及免疫细胞的自噬 [37]。此外,从PD病人和实验模型的证据表明,α-syn的聚合可以引发的先天免疫和适应性免疫 [38]。而神经炎症也可以促发α-syn的聚集 [39],这暗示着这两个过程都参与到一个自我的恶性循环当中。在当前的研究中,免疫疗法靶标α-syn正在临床实验中进行探索,这主要依赖于通过激活免疫细胞清除抗体结合的α-syn [40]。另外,由与PD家族形式相关的基因编码的几种蛋白质,包括α突触核蛋白(PARK1和PARK4)、帕金蛋白(PARK2)、DJ-1 (PARK7)和ATPase 13A2 (ATP13A2基因),都参与调控小胶质细胞和星形胶质细胞的激活 [41]。在PD患者的黑质中可观察到小胶质细胞的增量激活,并且小胶质细胞活化程度与早期PD中的多巴胺能性终末丢失相关 [42]。多巴胺能神经元周围的活化小胶质细胞通常是促炎性的 [43]。聚集的α-突触核蛋白从垂死的多巴胺能神经元中释放,并诱导小胶质细胞进入促炎性激活状态,促炎型小胶质细胞进而释放一系列促炎性细胞因子如TNF-α、NO和IL-1β,进而调节PD中的神经炎症 [44]。

2.8. 肠道菌群失调

肠道菌群与人类的行为、情绪有着奇妙的关联。帕金森病的非运动症状包括胃肠道功能障碍,主要表现为便秘和胃排空延迟。α-突触核蛋白异常聚集形成路易小体是帕金森病的细胞内病理学标志,研究发现,α-突触核蛋白不仅在在大脑中有表达,在肠道神经丛的神经元中也存在,因此,胃肠道进入帕金森病的研究领域。研究发现帕金森病患者表现出明显的肠道菌群失调,从而导致肠道菌群所产生的代谢产物及神经活性物质水平发生显著变化,如内毒素、神经毒素、细胞外过氧化物等,从而对肠道细胞和中枢神经功能造成损伤。肠道神经丛神经元中α-突触核蛋白病理性聚集和肠道菌群失调之间孰为因果尚需进一步研究,但肠道菌群失调已被认为是帕金森病的发病机制之一。

3. 疾病的治疗

针对帕金森病的发病机理与临床症状,疾病的治疗主要有靶点药物治疗、物理治疗、干细胞治疗、运动治疗等方式。

3.1. 药物治疗

3.1.1. 左旋多巴(L-DOPA)

左旋多巴是现有的治疗PD的一个较好的药物,在脑内可转变为多巴胺,从而补充纹状体中多巴胺的不足,随着时间的推移,几乎所有的帕金森病人都会使用这种药物进行治疗 [45]。然而,它的使用也伴随着一些并发症,如药物诱导的运动障碍、失眠、焦虑等 [46]。

3.1.2. 儿茶酚-O-甲基转移酶抑制剂

儿茶酚-O-甲基转移酶抑制剂可抑制外周多巴胺的代谢,提高生物利用率,增加L-DOPA的半衰期,延长L-DOPA的利用时间,从而辅助L-DOPA起到抗PD作用,目前已经有3种儿茶酚-O-甲基转移酶抑制剂可供临床使用 [47]。

3.1.3. 单胺氧化酶B型抑制剂

在胶质细胞中,通过单胺氧化酶B (MAOB)氧化是清除突触释放的多巴胺的主要机制,仅次于多巴胺转运体的突触前再摄取 [48]。抑制MAOB可增加突触多巴胺的浓度,具有一定的抗帕金森病疗效 [49]。

3.1.4. 多巴胺受体激动剂

纹状体棘突神经元中多巴胺的作用是通过两类多巴胺受体介导的。多巴胺受体激动剂直接作用于多巴胺受体,主要针对D2受体家族 [50]。相比于L-DOPA,多巴胺受体激动剂使纹状体多巴胺受体受到的刺激更少,作为治疗帕金森疾病的单一疗法使诱导运动并发症的风险显著降低 [50] [51]。

3.2. 物理治疗

深部脑刺激(deep brain stimulation),简称DBS,可通过高频(100~200 hz)电刺激特定的大脑部位模拟病变,且不会破坏脑组织。1993年,被发现可用于治疗帕金森病 [52],主要针对晚期帕金森病的运动波动和运动障碍的循证治疗。深部脑刺激诱导的改善与之前左旋多巴的治疗反应有关,也就是说,对多巴胺能治疗没有反应的患者不太可能对DBS做出反应。

DBS是一种复杂的物理治疗方法,需要正确植入电极、术后编程、神经刺激和药物治疗调整等多方面高水平的跨学科专业知识 [53]。常见的不良事件是颅内出血和设备并发症(如感染和铅中毒等) [54]。

3.3. 干细胞治疗

人类诱导多能干细胞(hiPSCs)和人类胚胎干细胞(hESCs)是研究神经退行性疾病的两种新型细胞来源 [55]。由hiPSCs/hESCs诱导的多巴胺能神经元在帕金森病(PD)研究中非常有用,包括细胞替代疗法、疾病建模和药物筛选。近年来,对hiPSCs/hESCs在PD研究中的应用进行了大量的研究并取得了显著的进展,如再编程策略 [56] [57],以优化的方法产生高度均质的神经前体细胞,成熟的多巴胺能神经元在其中占有较大的比例 [58],移植后生存、整合状况良好 [59]。因此,诱导多能干细胞(iPSCs)和诱导神经干细胞(iNSCs)有望产生安全、同质、可扩展和可标准化的临床级DA神经细胞,可能会在未来应用细胞疗法治疗帕金森病的临床试验中发挥重要作用 [56]。

3.4. 运动治疗

由于帕金森疾病表现为明显的运动障碍,因此,除药物治疗外,辅助一些运动训练,如步态、平衡控制、肌肉力量训练可作为缓解治疗的一种方式 [60] [61]。此外,有研究表明,病人生活质量的提高对帕金森疾病的缓解也有一定的改善 [62]。

4. 面对的挑战

在未来PD的研究中最大的挑战是环境和生活方式因素,比如环境污染、饮食习惯、锻炼、吸烟等 [63]。因为人口的众多性,这些因素变得不可控,也无法具体、准确的统计。但它会在一定程度上影响神经系统的表观基因组。

第二个挑战是PD可能是一种多因素疾病,可能最后导致的结果(α-syn聚集和黑质的退行性病变)是一致的,但不同的患者上游致病的分子机制和他们下游的效应可能是不同的,因此,需要探究多靶点、系统性的治疗策略。

第三,帕金森病的症状、临床病程和神经病理学的差异,支持了多种形式的分子发病机制并存于疾病诊断领域的观点,使疾病的诊断变得复杂。

第四,疾病的发生发展可能需要同时激活多种的致病途径,从而使得某些细胞防御机制失灵,机制的探究变的更为困难。

最后,叠加在多个触发点和失败防御之间的复杂相互作用是正常细胞老化的过程。帕金森病的最大风险因素是年龄的增长,这也是难以避免的。所有的这些都使得PD的研究更加艰难。

5. 结语

总的来说,帕金森病是一种多因素介导的疾病,因此,帕金森病的治疗不能仅仅是针对某个靶点,而应该是探究多靶点、系统性的治疗策略,从而提高患者的生活质量。这也将是未来研究的重点与难点。

文章引用: 姜育辉 , 刘晓宇 , 周胜鸾 , 杨宇民 (2021) 帕金森病的致病因素及治疗。 生物过程, 11, 67-75. doi: 10.12677/BP.2021.114008

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